Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and the major cause of non-traumatic neurological disability in young adults in the USA. The classical view of MS as a white matter disease has recently been extended to include gray matter demyelination. The clinical impact of gray matter demyelination may explain why white matter lesions detected by brain imaging poorly correlate with neurological disability in MS patients. Greater than 50% of MS patients are cognitively impaired and their cognitive dysfunction has a greater impact on quality of life than physical disability. Recent studies of postmortem MS brains have established that hippocampal demyelination disrupts the maintenance of excitatory synapses and activation of neuronal signaling cascades that modulate memory and learning. Hippocampal demyelination is a likely cause of cognitive decline in MS patients. To confirm and extend this hypothesis, we have successfully developed a mouse model of hippocampal demyelination and established that these mice have reduced memory/learning, reduced synaptic densities, reduced neuronal proteins that modulate memory/learning and reduced long term potentiation (LTP). Remyelination reversed these changes. The studies outlined in this proposal are designed to unravel the sequence of neuronal changes in demyelinated hippocampi that contribute to neuronal dysfunction and memory impairment. We utilize a multidisciplinary approach to correlate behavioral, electrophysiological, biochemical, morphological, and in vivo imaging changes in demyelinated hippocampi and will determine if remyelination reverses documented changes. Our studies are translational and should identify potential therapeutic targets that could reduce or delay cognitive decline in MS patients. Our mouse model should also provide a platform for proof of principle testing of therapies designed to improve cognition in MS patients.